PERSPECTIVE SERIES Lymphocyte signal transduction Gary Koretzky, Series Editor ITAMs versus ITIMs: striking a balance during cell regulation Daniel D. Billadeau1,2 and Paul J. Leibson2 1Division of Developmental Oncology Research, and 2Department of Immunology, Mayo Graduate and Medical Schools, Mayo Clinic, Rochester, Minnesota, USA Address correspondence to: Paul J. Leibson, Department of Immunology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA. Phone: (507) 284-4563; Fax: (507) 284-1637; E-mail:
[email protected]. J. Clin. Invest. 109:161–168 (2002). DOI:10.1172/JCI200214843. Functional immune responses evolve through an ITAMs exquisitely controlled process integrating signals The activation of many immune cell types occurs from activating and inhibitory receptors on the through multisubunit cell-surface receptors in which immune cell surface. These complex interactions, antigen-recognizing or ligand-binding subunits are which regulate both the quality and magnitude of the noncovalently associated with one or more transmem- ultimate response, depend crucially on two short, brane adapter molecules. These transmembrane loosely conserved motifs found in the intracellular adapter molecules contain a short extracellular region, domain of various signaling proteins. These motifs, a transmembrane segment, and a cytoplasmic tail of termed “ITAMs” and “ITIMs” for immunoreceptor varying length. Adapters associated with the T cell tyrosine-based activation (or inhibititory) motifs, pro- receptor (TCR), BCR, several activating natural killer vide the basis for two opposed signaling modules that (NK) cell receptors, some Fc receptors, and other recep- duel for control of cellular activation within the tors on hematopoietic cells help transduce signals to immune system. these various cell types.